The major clinical abnormality associated with REM sleep is the obstructive sleep apnea syndrome manifested by the upper airway musculature. Little is known about specific neural pathways to the motoneurons of the upper airway muscles that contribute to the production of apneas. This proposal will examine two major hypotheses for differential suppression of upper-airway motoneuron pools during REM sleep: 1) these differential effects reflect different projections from the caudal raphe nuclei that mediate state-dependent changes to different upper airway motoneuron pools; and 2) these differential effects reflect different neurotransmitter receptor distributions in different upper airway motoneuron pools. To examine different upper airway motoneuron pools, we will study pathways to the hypoglossal nucleus (Mo12) and motor trigeminal nucleus (Mo5). Caudal raphe neurons globally modulate motor function at the level of the motoneuron, and the activities of caudal raphe neurons are state-dependent, with neuronal activity at a nadir specifically during REM sleep. Individual caudal raphe neurons may have diverse axonal trajectories, and thereby potentially innervate many cranial motor nuclei. Many caudal raphe neurons are serotonergic, and serotonin (5HT) is facilitory to upper airway cranial motoneurons. However, the caudal raphe nuclei also employ many other neurotransmitters, some of which are colocalized to varying degrees with 5HT and with each other. The broad range of physiological processes that raphe neurons participate in, and their neurochemical diversity suggests there must exist a distinct, cellular organization of the caudal raphe nuclei that mediates quite varied physiological functions. Elucidating the microcircuitry of those particular caudal raphe neurons projecting to the upper airway cranial motor nuclei is one major goal of this proposal. To achieve a more complete understanding of the pathways from the caudal raphe nuclei to the upper airway motoneuron pools, we have four specific aims: 1) To demonstrate that single caudal raphe neurons project to both the Mo5 and the Mol2 (Protocol I), and determine the neurochemical identity of this subset of caudal raphe neurons that project to these different upper airway motoneuron pools (Protocol III). 2) To determine the neurochemical identity of non-5HT caudal raphe afferents to the Mol2 (Protocol II), since both 5HT and non-5HT neuronal afferents project from the caudal raphe nuclei to the Mol2. 3) To determine the densities of 5HT1C, 5HT2, TRH and substance P receptors in the divisions of the Mo5 and Mol2 (Protocol IV) and demonstrate their presence on cranial motoneurons rather than other cytoarchitectural elements (Protocol V). 4) To demonstrate different terminal bouton distributions upon motoneurons differentially innervated by caudal raphe neurons (Protocol VI).